Targeted Agent Turns in Mixed Results in NSCLC

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These studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Survival failed to improve in a prospective study of patients with heavily treated non-small cell lung cancer (NSCLC) when they received the multikinase inhibitor sorafenib, although improvements were seen in progression-free survival and overall response rate

Point out that in a separate substudy analysis, a significant difference in progression-free survival and overall survival was found among patients with mutant versus wild-type EGFR treated with sorafenib.

Whether they received sorafenib or a matching placebo, patients had an overall survival (OS) of about 6 months, according to Luis Paz-Ares, MD, of Virgen del Rocio University Hospital in Seville, Spain.

However, multiple secondary endpoints did show significant advantages for the targeted agent, including progression-free survival (PFS), time to progression (TTP), overall response rate (ORR), and disease control rate (P<0.001 to P<0.0001 for all comparisons), he said during a presentation at the European Society for Medical Oncology (ESMO) meeting.

In a second ESMO presentation, researchers also found reason for optimism from a substudy biomarker analysis suggesting a survival benefit in patients with epidermal growth factor receptor (EGFR)-mutant NSCLC treated with sorafenib.

"There are data suggesting relevant anti-tumor activity of the drug, including PFS," said Paz-Ares during an ESMO press conference.

"The fact that there is no significant impact on OS highlights the increasing importance of post-study therapies in lung cancer trials. In addition, one cannot exclude a potential OS benefit in some patient populations," he added.

The rationale for evaluating sorafenib in advanced NSCLC came from a previous randomized trial that demonstrated activity in patients who had progressed after two or three prior chemotherapy regimens.

Investigators in Europe, Asia, and North America enrolled patients who were eligible for third- or fourth-line therapy, and randomized them to best supportive care with or without sorafenib. Treatment continued until disease progression, and the primary outcome was OS.

The randomized population consisted of 703 patients. In general, the groups were balanced in terms of baseline characteristics.

When the trial ended, the median OS was almost identical between the treatment groups: 248 days with sorafenib and 253 days with best supportive care alone.

A related presentation at the meeting focused on the possible patient subgroups that might derive a survival benefit from sorafenib, as Paz-Ares suggested.

For the subanalysis, the trial investigators, led by Tony Mok, MD, of the Chinese University of Hong Kong, performed a post-study exploratory examination of tumor or plasma mutation data obtained from 347 patients. They found EGFR mutations in 26% of the patients and KRAS mutations in 20%.

The results showed a significant difference in PFS and OS among patients with mutant versus wild-type EGFR treated with sorafenib, Mok said. Response to sorafenib did not vary by KRAS status.

Patients with EGFR-mutant NSCLC treated with sorafenib had a median OS of 423 days compared with 197 days for patients who received only best supportive care (HR 0.48, P=0.002). In contrast, OS was indistinguishable between treatment groups for patients with wild-type EGFR. The median OS was 253 days with sorafenib and 256 days with best supportive care.

Investigators found a significant interaction between biomarker status and response to treatment (P=0.023).

Patients with EGFR-mutant NSCLC had a median PFS of 83 days with sorafenib and 42 days with placebo (HR 0.27, P<0.001). Unlike the OS results, a PFS benefit emerged for patients with wild-type EGFR randomized to sorafenib (82 versus 46 days, HR 0.62, P<0.001).

"This is only an exploratory analysis and thus cannot confirm the value of EGFR mutation," Mok cautioned. "The biomarker population is small and might not necessarily be representative of the overall population."

But "contrary to prior suggestions, we confirmed that KRAS is not predictive of response to sorafenib," he added.

ESMO spokesperson Rafael Rosell, MD, noted that sorafenib also inhibits BRAF, VEGFR, and platelet-derived growth factor receptor (PDGFR). Inhibition of one or more of those genes might account for the survival benefit observed in the patients with EGFR mutations, particularly BRAF and MEK.

"In my opinion, the significant benefit of sorafenib in the subgroup of patients with EGFR-mutant tumors is a great breakthrough that merits validation in a prospective study," Rosell said in a statement.

"The use of sorafenib in the second-line setting may provide benefit in patients progressing after treatment with EGFR tyrosine kinase inhibitors," he added.

The study was supported by Bayer Healthcare and Onyx, and investigators in the trial included Bayer employees.

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